The present invention relates to novel nitroimidazooxazines, to their preparation, and to their use as drugs for treating Mycobacterium tuberculosis and other microbial infections, either alone or in combination with other anti-infective treatments.
Tuberculosis remains a leading infectious cause of death worldwide (mortality estimated to be 1.3 million in 2008), with a recent resurgence attributable to an enhanced susceptibility in HIV patients, the increasing incidence of multidrug-resistant strains and the emergence of extensively drug resistant strains. Current drug therapy for tuberculosis is long and complex, involving multidrug combinations (usually isoniazid, rifampin, pyrazinamide and ethambutol) given daily for in excess of 6 months. Furthermore, these drugs are relatively ineffective against the persistent form of the disease, which is suggested to occur in a significant proportion of cases (Ferrara et al., 2006). Second-line drugs used in lengthy combination therapies for multidrug resistant disease (typically over 2 years) mostly have reduced potency or greater toxicity than existing first-line agents. Frequently, incomplete treatment is administered, leading to high relapse rates and increased drug resistance, underscoring the urgent need for new, more effective drugs.
It is an object of the present invention to provide new nitroimidazooxazines with unexpectedly high potency against both aerobic (replicating) and hypoxic (latent or persistent) cultures of Mycobacterium tuberculosis and unexpectedly high efficacy in mouse models of Mycobacterium tuberculosis infection for use as anti-tubercular drugs and for the treatment of other microbial infections.